In man, normal urinary bladder contractions are mediated, in part, through cholinergic muscarinic receptor stimulation. Muscarinic receptors not only mediate, in part, normal bladder contractions, but also may mediate the main part of the contractions in the overactive bladder resulting in symptoms such as urinary frequency, urgency and urge urinary incontinence.
After administration of Fesoterodine and other phenolic monoesters of formula (I) to mammals, such as humans, these compounds are cleaved to form the Active Metabolite within the body. The Active Metabolite is known to be a potent and competitive muscarinic receptor antagonist (WO 94/11337). Fesoterodine and other phenolic esters of the formula (I) thus represent potential prodrugs for the Active Metabolite, and are effective drugs for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency, as well as detrusor hyperactivity (as described in U.S. Pat. No. 6,713,464 and EP-B-1,077,912).
A synthetic approach for the production of the Active Metabolite and monoesters of the phenolic hydroxy group of the Active Metabolite such as Fesoterodine has been described in U.S. Pat. No. 6,713,464 as follows:
In a first step, an ethereal solution is prepared from R-(−)-[3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl]-diisopropylamine, ethyl bromide and magnesium; this solution is diluted with dry THF and is cooled to −60 C.
In a second step, powdered solid carbon dioxide is added in small portions and the reaction mixture is warmed to room temperature.
In a third step, the reaction is quenched with an aqueous solution of ammonium chloride.
In a fourth step, the aqueous phase of the quenched reaction mixture is adjusted to pH 0.95.
In a fifth step, the pH adjusted phase is filtered and R-(−)-4-benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)-benzoic acid hydrochloride can be recovered from the solid.
In a sixth step, the resulting purified benzoic acid is esterified to its corresponding methyl ester. A diagram summarizing this multi-step synthesis is shown below.

U.S. Pat. No. 6,713,464 further describes converting the methyl ester to the Active Metabolite, and then esterifying the Active Metabolite to a phenolic monoester, such as Fesoterodine.
WO 94/11337 also describes a multi-stage process to synthesize the precursor to the Active Metabolite.
These previously described methods for producing the Active Metabolite require numerous steps that result in complex purification procedures, time-delay, and enhanced possibility of human error, thereby prohibiting optimal efficiency and cost-effectiveness. Also, the solid carbon dioxide used in the art is difficult to handle on large scale due to the need to work at very low temperatures and to add the crushed dry ice portion wise, and due to the difficulties to control the very exothermic nature of the reaction.
The present disclosure aims to overcome these problems and disadvantages. It has been found, and this forms one aspect of the present disclosure, that the use of a di(C1-C6 alkyl)carbonate, preferably dimethylcarbonate, in the Grignard reaction results in a highly pure product, while at the same time eliminating the production of the benzoic acid and the purification thereof.
This is surprising since current and well-known textbooks teach that the addition of Grignard reagents to carbonates and other esters produces tertiary alcohols as a predominant product. For example, in F. A. Carey, R. J. Sundberg, “Advanced Organic Chemistry”, Springer Media, 2001, it is taught that the addition of Grignard reagents to esters (including carbonates) is commonly used to produce tertiary alcohols (pages 447-448). Likewise, the well-known compendium “March's Advanced Organic Chemistry”, Wilex-Interscience Publication, John Wiley & Sons, Inc., 5th edition, 2001, page 1214, teaches that in Grignard reactions “carbonates give tertiary alcohol in which all three R groups are the same” (page 1214).
In a second aspect of the presently disclosed method, a further increase in reaction speed, yield and purity was achieved using a combination of a so-called Turbo Grignard reagent and extra Magnesium in such a Grignard reaction.
Recently, Knochel and co-workers (EP 1 582 523) described a reagent for use in the preparation of organomagnesium compounds, which reagent is designated as “Turbo Grignard reagent” in this application. They found that by using a mixed organometallic compound of the following formula (II)R1(MgX)n.LiY  (II)wherein n is 1 or 2; R1 is a substituted or unsubstituted C4-24-aryl or C3-24-heteroaryl, containing one or more heteroatoms as B, O, N, S, Se or P; linear or branched, substituted or unsubstituted C1-20 alkyl, C1-20 alkenyl, C1-20 alkynyl; or substituted or unsubstituted C3-20 cycloalkyl; or a derivative thereof; X and Y are independently or both Cl, Br or I, preferably Cl;
a fast exchange reaction occurs leading to the desired Grignard reagents in high yields under mild conditions and allowing the preparation of many functionalized Grignard compounds which were previously only available via Br/Mg-exchange reactions in mediocre yields.
Conversions which were conducted with e.g. iPrMgCl.LiC1 resulted in improved yields and in a shortened reaction time with high purity. Although the mechanism of the catalysis is not elucidated, Knochel et al. assumed that the role of lithium chloride is to activate iPrMgCl by increasing the nucleophilic character of the isopropyl group by forming a magnesiate species leading via an intermediate finally to the organomagnesium species PhMgCl.LiCl.

The complexation of the arylmagnesium may be responsible for the enhanced reactivity of these magnesium organometallics.
The present application discloses that the use of iPrMgCl.LiCl in conjunction with additional Mg in the process of preparing of 2-(3-diisopropylamino-1-phenylpropyl)-4-(hydroxymethyl)-phenol (“Active Metabolite”) and its phenolic monoesters of formula (I) results in a increased yield and purity in comparison to conventional Grignard reagents or compared to the sole use of Turbo Grignard reagents without extra Mg. When the Turbo Grignard reagent was used solely, long reaction times were required and thus a great risk of impurity formation, in particular due to moisture ingress and subsequent formation of a des-bromo by-product. Surprisingly, the addition of magnesium resulted in a marked increase in both reaction rate and subsequent overall reaction yield and purity and thus provides a more efficient synthetic approach to compounds of formula (I).